Macular dystrophy is a term applied to a heterogeneous group of diseases that collectively are the cause of severe visual loss in a large number of people. A common characteristic of macular dystrophy is a progressive loss of central vision resulting from the degeneration of the pigmented epithelium underlying the retinal macula. In many forms of macular dystrophy, the end stage of the disease results in legal blindness. More than 20 types of macular dystrophy are known: e.g., age-related macular dystrophy, Stargardt's disease, atypical vitelliform macular dystrophy (VMD1), Usher Syndrome Type 1B, autosomal dominant neovascular inflammatory vitreoretinopathy, familial exudative vitreoretinopathy, and Best's macular dystrophy (also known as hereditary macular dystrophy or Best's vitelliform macular dystrophy (VMD2)). For a review of the macular dystrophies, see Sullivan & Daiger, 1996, Mol. Med. Today 2:380–386.
Best's Macular Dystrophy (BMD) is an inherited autosomal dominant macular dystrophy of unknown biochemical cause. BMD has an age of onset that can range from childhood to after 40. Clinical symptoms include, at early stages, an abnormal accumulation of the yellowish material lipofuscin in the retinal pigmented epithelium (RPE) underlying the macula. This gives rise to a characteristic “egg yolk” appearance of the RPE and gradual loss of visual acuity. With increasing age, the RPE becomes more and more disorganized, as the lipofuscin accumulations disperse and scarring and neovascularization take place. These changes are accompanied by further loss of vision.
The pathological features seen in BMD are in many ways similar to the features seen in age-related macular dystrophy, the leading cause of blindness in older patients in the developed world. Age-related macular dystrophy is an extraordinarily difficult disease to study genetically, since by the time patients are diagnosed, their parents are usually no longer living and their children are still asymptomatic. Thus, family studies which have led to the discovery of the genetic basis of many other diseases have not been practical for age-related macular dystrophy. As there are currently no widely effective treatments for age-related macular dystrophy, it is hoped that study of BMD, and in particular the discovery of the underlying genetic cause of BMD, will shed light on age-related macular dystrophy as well.
Linkage analysis has established that the gene responsible for BMD resides in the pericentric region of chromosome 11, at 11q13, near the markers D11S956, FCER1B, and UGB (Forsman et al., 1992, Clin. Genet. 42:156–159; Hou et al., 1996, Human Heredity 46:211–220). Recently, the gene responsible for BMD was localized to a ˜1.7 mB PAC contig lying mostly between the markers D11S1765 and UGB (Cooper et al., 1997, Genomics 41:185–192). Recombination breakpoint mapping in a large Swedish pedigree limited the minimum genetic region containing the BMD gene to a 980 kb interval flanked by the microsatellite markers D11S4076 and UGB (Graff et al., 1997, Hum. Genet. 101: 263–279).
One difficulty in diagnosing BMD is that carriers of the diseased gene for BMD may be asymptomatic in terms of visual acuity and morphological changes of the RPE observable in a routine ophthalmologic examination. There does exist a test, the electro-oculographic examination (EOG), which detects differences in electrical potential between the cornea and the retina, that can distinguish asymptomatic BMD patients from normal individuals. However, the EOG requires specialized, expensive equipment, is difficult to administer, and requires that the patient be present at the site of the equipment when the test is performed. It would be valuable to have an alternative method of diagnosing asymptomatic carriers of mutations in the gene responsible for BMD that is simpler, less expensive, and does not require the presence of the patient while the test is being performed. For example, a diagnostic test that relies on a blood sample from a patient suspected of being an asymptomatic carrier of BMD would be ideal.